During neurodevelopment, more neurons are initially generated than are necessary. To prune away these superfluous neurons, neuronal death is required. While loss of neurons is necessary during development, neuronal death in the adult nervous system is highly detrimental, as these neurons must persist for the lifetime of the organism. As such, there need to exist tightly-regulated mechanisms that preserve neuronal viability. The identity of these pathways and whether they are perturbed in neurodegenerative disease remain poorly understood. The six-transmembrane protein GDE2 has been previously identified as a cell surface GPI-anchor cleaving enzyme that regulates Notch signaling during neurogenesis through the cleavage of GPI-anchored proteins. Recent evidence shows that levels of GDE2 and its GPI anchor-cleaving activity persist in the adult nervous system and that loss of GDE2 (Gde2-/-) results in slow, progressive neurodegeneration in mice. The proposed studies aim to define the neuropathology of Gde2-/- mice through immunohistochemical and biochemical analyses, to identify the downstream GPI-anchored proteins that mediate the neuroprotective function of GDE2, and to determine relevance for GDE2 dysfunction in human neurodegenerative diseases. Preliminary evidence identifies a target for GDE2 that mediates neuronal survival and demonstrates its altered processing in Alzheimer's disease patients. Taken together, these data suggest that GDE2 may regulate an important neuroprotective pathway that is perturbed in Alzheimer's disease. As the aging population grows, so too will the need for solutions to aging-associated diseases. With 5.3 million people afflicted with Alzheimer's disease in the U.S. alone and the annual rate of disease-related deaths increasing every year, finding an effective treatment for Alzheimer's disease is crucial. Currently, Alzheimer's disease is being treated palliatively, and recent clinical trials have generally been ineffective, with most targeting behavioral symptoms or terminal pathologic features. Accordingly, there is a dire need for mechanism-based therapies and biomarkers that detect early signs of decline in patients. The proposed studies may uncover the potential for GDE2 and its GPI-anchored substrates as exciting and promising avenues for research in the quest for next generation Alzheimer's disease therapeutic targets and fluid biomarkers.